Glipizide

Glipizide is an Antidiabetic Agent belonging to the pharmacology class of second-generation sulfonylureas.

Glipizide is approved for treating type 2 diabetes mellitus. Glipizide helps lower blood sugar levels by stimulating the pancreas to release more insulin, thus improving glucose control in diabetes.

Glipizide is rapidly absorbed after oral administration, reaching peak plasma concentrations in about 1-3 hours. It undergoes extensive metabolism in the liver, forming inactive metabolites. The elimination half-life is approximately 2-4 hours. About 90% of the dose is primarily excreted in the urine as metabolites.

Glipizide's most common side effects include diarrhoea, nervousness, tremors, and flatulence.

Glipizide is available in the form of Tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Germany and Australia.

Glipizide is an Antidiabetic Agent belonging to the pharmacology class of second-generation sulfonylureas. A chronic metabolic condition with rising incidence globally is type 2 diabetes mellitus (T2DM). T2DM is a complicated condition characterised by blood glucose levels that are higher than expected and result from genetic, environmental, and behavioural risk factors. The peptide hormone insulin is an essential part of controlling blood sugar levels. When blood sugar levels are high, insulin encourages the absorption of glucose into the liver, muscle cells, and fat cells for storage. Several different factors cause T2DM's pathophysiology. Still, the primary ones are insulin resistance, diminishing insulin production, and eventually failing beta cells in the pancreatic islets, which create insulin regularly. The risk of long-term secondary consequences, such as cardiovascular mortality, must be managed early with lifestyle interventions like restricted diet and exercise. Like other sulfonylurea medications, glipizide functions as an insulin secretagogue, causing the pancreatic beta cells to produce more insulin and raising the insulin level in the blood. Therefore, the drug's primary therapeutic effect depends on the pancreatic islets' functioning beta cells. Sulfonylureas binds to the sulfonylurea receptor expressed on the plasma membrane of pancreatic beta-cells, which causes the ATP-sensitive potassium channel to close and the potassium conductance to decrease. As a result, the voltage-sensitive calcium channels open, depolarizing the pancreatic beta cell and facilitating calcium ion influx. The production of insulin granules from beta cells, also known as exocytosis, is stimulated by elevated intracellular calcium ion concentrations. In addition to this primary mode of action, glipizide also lowers blood sugar levels by increasing the number and sensitivity of insulin receptors and promoting hepatic gluconeogenesis.

Glipizide is available in tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Glipizide treats type 2 diabetes, characterized by high blood sugar levels. When used in combination with a healthy diet and exercise, this helps people with type 2 diabetes reduce their blood sugar levels and can improve glycemic control. Usually, glipizide is recommended when dietary modifications alone are insufficient to control diabetes.

In Treatment of Type 2 diabetes mellitus

Glipizide helps boost the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of developing any significant consequences of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

Treatment of diabetes mellitus, type 2: Glipizide is indicated as an adjunct to exercise and diet to help persons with type 2 diabetes mellitus regulate their blood sugar levels.

Orally: Glipizide is available as a tablet that can be taken orally. Glipizide should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablet: 5mg, 10mg

Tablet, extended-release: 2.5mg, 5mg, 10mg

Glipizide is available in the form of Oral Tablets

Dose Adjustment in Adult Patients:

Type 2 Diabetes Mellitus

Immediate-release tablet: 5 mg PO qDay at initial administration, followed by 2.5–5 mg PRN every several days, depending on blood sugar

2.5–20 mg PO per day or every 12 hours for maintenance; not to exceed 40 mg per day.

Extended-release tablets:

5 mg PO qDay at initial administration with breakfast; dosage modification depending on blood glucose should not occur more frequently than once every seven days.

5-10 mg PO qDay for maintenance; not to exceed 20 mg/day.

Dosing Considerations

Doses above 15 mg: Oral divided every 12 hours is advised.

Glipizide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Glipizide, avoid consumption of a high-salt or high-sodium in the diet, and be cautious of high-sodium processed foods.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages.

It is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Glipizide may be contraindicated in the following conditions:-

• Known hypersensitivity to glipizide or any of the product’s ingredients.

• Hypersensitivity to sulfonamide derivatives.

• Type 1 diabetes

• Diabetic ketoacidosis with or without coma

• Hypoglycemia: Glipizide should be used with caution in individuals who are at risk for developing severe hypoglycemia, such as the elderly, the weak or malnourished, those who have adrenal or pituitary insufficiency, and those who are under stress from an illness, a fever, trauma, or surgery. Beta-blockers or sympatholytic drugs may make it more challenging to detect hypoglycemia.
• When calorie intake is insufficient, after intense or prolonged activity, when alcohol is used, or when several glucose-lowering medications are taken, hypoglycemia is more likely to happen.
• Hemolytic Anemia: Hemolytic anaemia may arise in people treated with sulfonylurea medications for glucose 6-phosphate dehydrogenase (G6PD) insufficiency, such as glipizide extended-release pills. Glipizide extended-release pills shouldn't be taken by those who have G6PD deficiency. Hemolytic anaemia has also been reported in post-marketing studies in individuals who did not have a known G6PD deficiency.
• Patients with severe gastrointestinal narrowing or oesophagal dysmotility should not use extended-release tablets.
• Increased Risk of Cardiovascular Mortality with Sulfonylurea, but data is limited.
• It may be required to stop taking glipizide and start insulin treatment during times of stress like fever, trauma, illness, or surgery to regulate blood sugar levels effectively.

It is unsafe to consume Glipizide with alcohol.

Caution during breastfeeding. Breastfeeding should be avoided until the mother's therapy is finished and the medication has been completely removed from her body.

Increase intake of fibre-rich foods and minimize the carbohydrate or sugary intake.

The adverse reactions related to Glipizide can be categorized as

• Common Adverse Effects: Hypoglycemia, weight gain, nausea, and dizziness.
• Less Common Adverse effects: Constipation, skin rash, sensitivity to sunlight (photosensitivity) and elevated liver enzymes
• Rare Adverse Effects: Jaundice, hematologic disorders, severe skin reactions, or a dangerously low blood sugar level.

Reports on Postmarketing

Abdominal ache

Liver damage with jaundice-accompanied cholestasis and hepatocellular forms

Aplastic anaemia, hemolytic anaemia, thrombocytopenia, agranulocytosis, leukopenia, and pancytopenia.

Symptoms of disulfiram and hepatic porphyria

Rash Hyponatremia with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

There have been complaints of gastrointestinal discomfort and bleeding while using a different medication with this non-dissolvable extended-release formulation.

The clinically relevant drug interactions of Glipizide are briefly summarized here

Miconazole: There have been reports of a severe hypoglycemia-causing interaction between oral glipizide and miconazole. It is unknown if this interaction also happens while using the intravenous, topical, or vaginal formulations of miconazole.

Fluconazole: Fluconazole therapy given concurrently increases glipizide plasma level. Diflucan® (fluconazole) and glipizide were administered concurrently to healthy volunteers in placebo-controlled crossover research to show the impact. Glipizide was given to each individual alone, and after seven days of therapy, 100 mg of Diflucan®. After fluconazole delivery, the average percentage increase in the glipizide AUC was 56.9% (with a range of 35% to 81%).

Colesevelam: When co-administered with glipizide, colesevelam can lower both the maximum plasma concentration and total exposure. In trials examining the impact of colesevelam on the pharmacokinetics of glipizide ER in healthy individuals, colesevelam co-administration resulted in decreases in glipizide AUC0- and Cmax of 12% and 13%, respectively. No appreciable reduction in glipizide AUC0- or Cmax, -4% and 0%, was seen when glipizide ER was taken 4 hours before colesevelam.

• Pregnancy

Pregnancy Category B; Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been established by animal studies rather than human studies. However, sulfonylureas (including glipizide) pass the placenta and have been linked to neonatal adverse responses, including hypoglycemia; as a result, medication should be stopped for at least two weeks before planned birth. Poorly managed diabetes during pregnancy raises the risks for significant birth abnormalities, stillbirth, and macrosomia-related morbidity in the foetus and for the mother's diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery difficulties.

When gestational diabetes patients use sulfonylureas throughout pregnancy, their newborns may have an increased chance of being admitted to a neonatal critical care unit and may also experience respiratory distress, hypoglycemia, birth injuries, and be significant for gestational age; newborns born to women who received a sulfonylurea at the time of delivery have been reported to experience prolonged severe hypoglycemia, lasting 4-10 days, and this has been linked to the usage of long-acting medications; infants should be watched for signs of hypoglycemia and respiratory distress and treated appropriately.

Therapy should be stopped at least two weeks before the predicted delivery date due to reports of persistent severe hypoglycemia in newborns delivered to women taking sulfonylurea at the time of birth.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, pre-eclampsia, miscarriage, premature birth, stillbirth, and delivery problems. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are all made more likely in foetuses with poorly managed diabetes.

Adverse Fetal/Neonatal Reactions

Sulfonylurea-treated neonates of gestational diabetes patients may be more likely to require admission to a neonatal intensive care unit and be more likely to experience respiratory distress, hypoglycemia, birth injuries, and large-for-gestational-age size. In neonates delivered to women who received a sulfonylurea at the time of delivery and with medications with an extended half-life, severe hypoglycemia lasting 4 to 10 days has been seen. Monitor for signs of hypoglycemia and respiratory distress in neonates and take appropriate action.

Dose adjustments during pregnancy and the postpartum period

Glipizide extended-release tablets should be discontinued at least two weeks before the anticipated birth date due to reports of sustained severe hypoglycemia in neonates delivered to women taking sulfonylurea at the time of delivery.

Animal Data

In teratology investigations on pregnant rats and rabbits, glipizide was given orally daily at doses up to 2000 mg/kg/day and 10 mg/kg/day (corresponding to roughly 833 and 8 times the human dosage based on body surface area), respectively. The development of the embryo and foetus was unaffected by any of the tested dosages. In a pre-and postnatal investigation on pregnant rats, there was a decrease in the proportion of pups that survived after being given glipizide from gestation day 15 through lactation and weaning at dosages under 5 mg/kg/day (about double the maximum human dose advised based on body surface area).

• Nursing Mothers

Although glipizide was undetectable in human milk in a small clinical lactation study, this result is not conclusive due to the limitations of the assay used in the study. However, there is no data on the effects of glipizide on milk production; the developmental and health benefits of breastfeeding should be taken into consideration, along with the mother's clinical need for therapy and any potential adverse effects. Breastfed infants of lactating women on treatment should be monitored for symptoms of hypoglycemia.

Clinical Considerations

Monitoring for adverse reactions

The indications of hypoglycemia, such as jitters, cyanosis, apnea, hypothermia, extreme drowsiness, poor feeding, and seizures, should be maintained and monitored in breastfed newborns.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric

population have yet to be established.

• Geriatric Use

Dose Adjustment in Geriatric Patient

Diabetes

2.5 mg orally qDay initially; increase by 2.5-5 mg/day every 1-2 weeks as indicated by blood glucose response at intervals of several days.

At the lowest recommended dose or the nearest equivalent total daily dose, switching to extended-release once-daily tablets is possible; the daily maximum amount is 20 mg.

Dosing considerations

There is controversy about how closely glucose levels should be managed in older people since they are vulnerable to the hypoglycemic effects of glucose-lowering medications. For elderly patients, it may be challenging to recognise hypoglycemia.

Monitoring blood pressure and cholesterol may be more crucial than maintaining normalised glycemic control because these factors are linked to cardiovascular disease.

The amount administered for both initial and ongoing treatment should be moderate.

Dose Adjustment in Kidney Impairment Patient:

Hepatic impairment: Initial dose of 2.5 mg PO once per day (immediate release); prolonged release not investigated

Dose Adjustment in Hepatic Impairment Patients:

Renal impairment: Not known; if GFR <50 mL/min, it may decrease dose by 50% (suggested)

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Glipizide.

Overconsumption of Glipizide could lead to symptoms such as mild to moderate hypoglycemia, confusion, headache, fatigue, elevated blood pressure, and heart rhythm

Management

There is no specific antidote or treatment for excessive intake of Glipizide. However, immediate medical attention is essential. Glipizide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.

Management typically involves supportive measures and symptomatic treatment. The patient will continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Treatment with oral glucose is recommended for mild hypoglycemia symptoms without loss of consciousness or neurologic signs. Glucagon or intravenous glucose should also be administered to the patient.

Pharmacodynamics:

Blood sugar is lowered with the drug glipizide. The blood glucose-lowering effect begins approximately 30 minutes after delivery, and the products endure for between 12 and 24 hours. Even after six months of therapy, the postprandial insulin response, or insulin response to a meal, is improved by glipizide, even though long-term usage does not raise fasting insulin levels. However, glipizide also mediates specific extrapancreatic effects, such as the enhancement of insulin signalling effects on the muscles, fat, or liver cells. Glipizide's principal therapeutic activities predominantly occur in the pancreas, where insulin production is promoted. Sulfonylureas, such as glipizide, have been associated with a risk for hypoglycemia and weight gain in people taking the medication because of their effect on endogenous cells. The sulfonylurea receptors on pancreatic beta cells, which are the drug's molecular targets, maybe down-regulated due to chronic glipizide treatment, which would limit the drug's ability to increase insulin production.

Glucagon and somatostatin are peptide hormones that control neuroendocrine and metabolic processes, and glipizide, like other sulfonylureas, may act on pancreatic alpha (α) and delta (δ) cells to promote and decrease, respectively, their respective secretions. Like other members of the sulfonylurea medication class, glipizide also has additional biological effects outside the pancreas, or "extrapancreatic effects," in addition to its primary action on the pancreas. Glipizide may increase glucose absorption into skeletal muscles and increase insulin's effect on the liver. Other effects include decreased hepatic glucose production, reduced liver and adipose tissue lipolysis, and enhanced glucose absorption and oxidation. Additionally, several studies have shown that the prolonged therapeutic use of sulfonylureas may increase insulin receptor expression in erythrocytes, adipocytes, and monocytes.

Pharmacokinetics:

Absorption

Glipizide is consistently, rapidly, and completely absorbed in the gastrointestinal tract. When given orally to patients with type 2 diabetes, glipizide had a 100% absolute bioavailability. Within 6 to 12 hours after the first dose, the maximum plasma concentrations are anticipated to be attained. The steady-state plasma concentrations of glipizide from extended-release oral formulations remain constant throughout the duration of the 24-hour dosing period. The presence of meals in healthy participants slowed the absorption of glipizide, although the overall absorption was unaffected.

Bioavailability: 100%

Onset: Initial effect at 30 min and max effect at 2-3 hr

Peak plasma time: 1-3 hr (IR); 6-12 hr (ER)

Duration: 12-24 hr

Distribution

After giving single doses to individuals with type 2 diabetes mellitus, the mean volume of distribution was around 10 L. The amount of the drug and its metabolites found in the foetuses of pregnant female mice and rats was negligible to nonexistent in these trials. The risk of glipizide in foetuses or babies cannot be completely ruled out because other sulfonylurea medications have been proven to pass through the placenta and into breast milk.

Protein bound: 99%

Vd: 10-11 L

Metabolism

The primary metabolites of glipizide are produced through aromatic hydroxylation in the liver, where glipizide is vulnerable to metabolism. It has been found that these principal glipizide metabolites are pharmacologically inactive. In contrast, a minor metabolite called acetylaminoethyl benzine, which makes up less than 2% of the original dosage and has one-tenth to one-third as much hypoglycemic effect as the parent chemical, is generated. Albumin is the primary plasma protein to which glipizide is 98–99% bound in blood proteins.

Excretion

Less than 10% of the original dose of the medication can be found in the urine and faeces as unchanged glipizide, which is mainly removed through hepatic biotransformation. Glipizide's metabolites are eliminated in the urine in around 80% of cases and the faeces in 10%.

Half-life: 2-5 hr

Excretion: Urine (63-90%); feces: (10%)

• Simonson, D C et al. “Efficacy, safety, and the dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. The Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide Gastrointestinal Therapeutic System Study Group.” Diabetes care vol. 20,4 (1997): 597-606. doi:10.2337/diacare.20.4.597
• Aman, M et al. “Clinical trial with glipizide in uncomplicated maturity-onset diabetes mellitus.” JPMA. The Journal of the Pakistan Medical Association vol. 27,3 (1977): 293-5.
• Lebovitz, H E. “Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical use.” Pharmacotherapy vol. 5,2 (1985): 63-77. doi:10.1002/j.1875-9114.1985.tb03405.x
• Kitabchi, A E et al. “Comparative efficacy and potency of long-term therapy with glipizide or glyburide in patients with type 2 diabetes mellitus.” The American journal of the medical sciences vol. 319,3 (2000): 143-8. doi:10.1097/00000441-200003000-00003
• Fowler, L K. “Glipizide in the treatment of maturity-onset diabetes: a multi-centre, out-patient study.” Current medical research and opinion vol. 5,5 (1978): 418-23. doi:10.1185/03007997809111908

Carcinogenesis, Mutagenesis, Impairment of Fertility

No indication of drug-related carcinogenicity was found in studies conducted on rats and mice for 20 months and 18 months, respectively, at doses up to 75 times the maximum human dosage. In vivo and bacterial mutagenicity testing, all came out negative. Studies on rats of both sexes at dosages up to 20 times the human dose based on body surface area did not find any impact on fertility.

• Patients should be informed of the possible side effects of glipizide extended-release pills, including hypoglycemia. Inform patients and responsible family members about the risks of hypoglycemia, its signs, symptoms, and treatment, as well as the situations that make it more likely to occur. Consistently reinforce to patients the value of following dietary guidelines, participating in a regular exercise regimen, and checking their glycemic control regularly.

• Let patients know that the extended-release glipizide pills should be taken whole. Inform patients that they should not chew, split, or crush tablets and that they could occasionally find anything that resembles a tablet in their stools. The glipizide extended-release tablet contains the medication inside a non-dissolvable shell specifically made to release the drug gradually so the body may absorb it.

• Pregnancy: Encourage women capable of becoming pregnant to let their doctor know if they are pregnant or suspect they are pregnant.
• Lactation: Encourage mothers who are nursing and using glipizide extended-release tablets to keep watch for possible indications of hypoglycemia in their breastfed children, such as jitters, cyanosis, hypothermia, extreme drowsiness, poor eating, and seizures.

• https://www.ncbi.nlm.nih.gov/books/NBK459177/
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a430577c-f233-40a7-bfd8-3d2bc6f98aa2
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020664s011lbl.pdf
• https://pubmed.ncbi.nlm.nih.gov/6369968/